Cancer treatments targeting mutated oncoproteins have proven highly effective and are often associated with fewer side effects than conventional chemotherapy. The expansion of this paradigm of mutation- specific treatments continues to impact the treatment of a large diversity of cancers. In spite of these advances many tumor types and many genetic contexts remain refractory to such targeted approaches, chief among these are RAS mutant tumors. Furthermore, even when key mutant proteins are targeted resistance almost invariably develops. Thus, new approaches capable of delivering targeted interventions to a large fraction of cancer patients, independent of the tumors' mutational status and with lower rates of associated disease recurrence, are highly desirable. Here we propose a research program with the intent of developing a rational path towards reaching these important goals. It is well established that cancer cells of diverse tissue origin share a variety of critica features, including immortality, uncontrolled self- renewal, survival, motility, invasiveness, and cell metabolism. Notably, these features emerge in diverse cancers in response to a wide variety of oncogenic mutations. Such strong convergence in behavior suggests a critical role for mechanisms shared between diverse cancers that act downstream of mutant oncogenic drivers and mediate the malignant cell transformation process and/or maintain cancer cell homeostasis. Through analysis of the molecular mechanisms underlying oncogene cooperativity we have shown that the combined effect of multiple oncogenic mutations is mediated through synergistic regulation of so-called `cooperation response genes' (CRGs). Notably, these non-mutated genes downstream of oncogenic mutations are critical to the emergence of the cancer cell traits shared among diverse types of cancer. In depths functional analysis indicates that the majority of CRGs tested are critical to the cancer phenotype, and investigation of the processes they govern is revealing novel points of synthetic, cancer cell-specific vulnerability. Further, we are finding that many CRGs are similarly de-regulated in various cancers harboring a wide spectrum of oncogenic driver mutations. Notably, CRG expression patterns are also conserved in primary and recurrent cancers that have undergone a switch in oncogenic driver identity during disease progression. Our preliminary data are thus consistent with our central hypothesis that CRGs are critical to sustaining core features of a malignant state shared between diverse cancers. Understanding mechanisms underlying emergence and stability of cancer cell homeostasis, we believe, will hold great promise and unexpected opportunities for targeted and cancer cell-specific interventions independent of the identity of oncogenic driver mutations. We will be using genetically tractable in vivo and in vitro models in combination with genomic RNA expression and bioinformatics analyses to identify key regulatory pathways and circuits related to CRG activity in cancer cell homeostasis.